Medical implant

ABSTRACT

Disclosed is a self-expanding medical implant for placement within a lumen of a patient. The implant comprises a woven or non-woven structure having a substantially tubular configuration, and is designed to be low-profile such that it is deliverable with a small diameter catheter. The implant has a high recoverability and desired mechanical properties.

This application is a continuation-in-part of, and claims the benefit ofpriority to, U.S. patent application Ser. No. 12/783,261, filed May 19,2010, by inventors Lee Core et al., entitled “Medical Implant,” andfurther claims the benefit of priority to U.S. Patent Application61/179,834, filed May 20, 2009, by inventors Lee Core et al., entitled“Medical Implant,” to U.S. Patent Application 61/227,308, filed Jul. 21,2009, by inventors Lee Core et al., entitled “Medical Implant,” and toU.S. Patent Application 61/251,984, filed Oct. 15, 2009, by inventorsLee Core et al.

FIELD OF THE INVENTION

The present invention relates to medical implants, and morespecifically, to self-expanding medical implants that are intended forplacement within a lumen or cavity of a patient.

BACKGROUND

A variety of medical conditions are treatable by the implantation oftubular devices into natural body lumens. For example, it is commonplaceto implant metallic stents into the coronary arteries of patients withheart disease following balloon angioplasty to minimize the risk thatthe arteries will undergo restenosis. Recently, commercial stents haveincluded drug-eluting polymer coatings that are designed to furtherdecrease the risk of restenosis. Other examples of conventional tubularmedical implants include woven grafts and stent-grafts that are used tospan vascular aneurysms, polymeric tubes and catheters that are used tobypass strictures in the ureter and urethra, and stents that are used inthe peripheral vasculature, prostate, and esophagus.

Despite the evolution of metallic stents, they continue to havelimitations such as the possibility of causing thrombosis and vascularremodeling. While the use of biodegradable and biostable polymericmaterials for stents and other implantable devices has been proposed toeliminate the possible long-term effects of permanent implants, the useof such materials has been hindered by relatively poor expandability andmechanical properties. For example, the expansion characteristics andradial strength of prototype stents made from biodegradable andbiostable polymeric materials has been significantly lower than that ofmetallic stents. This is particularly the case where such stents are lowprofile and make use of small diameter fibers or thin walled struts thatcomprise the stent body. Furthermore, the degradation rate and themanner in which such devices degrade in the body has been difficult tocontrol. Finally, where such devices are used as a drug deliveryvehicle, the drug elution rate has been difficult to reproduciblycharacterize.

There is therefore a need for low-profile, self-expanding implantabletubular devices that have sufficient expansion characteristics, strengthand other mechanical and drug release properties that are necessary toeffectively treat the medical conditions for which they are used.

SUMMARY

In one aspect, the present invention includes an implantable medicaldevice for placement within a lumen or cavity of a patient. In anotheraspect, the present invention includes a method of loading the medicaldevice into a delivery catheter just prior to being implanted into apatient. In another aspect, the present invention includes a method oftreating a patient by delivering the medical device to a target locationwithin the patient. In yet another aspect, the present inventionincludes a kit that comprises the implantable medical device.

The implantable medical devices of the present invention are generallytubular, self-expanding devices. The devices have a combination ofstructure, composition, and/or strengthening means that provide themwith exceptional expandability and mechanical properties when comparedwith conventional self-expanding devices.

In one embodiment, the implantable medical device comprises aself-expanding tubular structure that comprises at least one strand. Theat least one strand comprises a first polymer characterized by a modulusof elasticity greater than about 1 GPa. The implantable medical devicefurther includes a strengthening means comprising a second polymer atleast partially coating the strand. The second polymer is characterizedby a percent elongation to break that is greater than about 150 percentat body temperature (37° C.). The second polymer increases the mass ofthe self-expanding tubular structure by at least about 20 percent.

In another embodiment, the implantable medical device comprises aself-expanding tubular structure that comprises at least one strandcomprising a first polymer. The implantable medical device furtherincludes a strengthening means comprising a second polymer at leastpartially coating the strand. The second polymer comprises a firstelastic component having a Tg less than about 37° C. and a secondcomponent that is harder than the first component. The second polymerincreases the mass of the self-expanding tubular structure by at leastabout 20 percent.

In other embodiments, the implantable medical device comprises aself-expanding tubular structure comprising a unitary framework ratherthan at least one strand. In certain embodiments, the implantablemedical device comprises a therapeutic agent for delivery into apatient's body.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of an implantable braided medical device, inaccordance with an embodiment of the present invention.

FIG. 2 is a side view of an implantable unitary framework medicaldevice, in accordance with an embodiment of the present invention.

FIG. 3 is a cross-sectional view of a strand of an implantable medicaldevice in accordance with an embodiment of the present invention thatincludes a support coating.

FIG. 4 is a side view of a strand of an implantable medical device inaccordance with an embodiment of the present invention that includesdiscrete areas of therapeutic agent thereon.

FIG. 5 is a cross-sectional view of a strand of an implantable medicaldevice in accordance with an embodiment of the present invention thatincludes a therapeutic agent coating and a topcoat.

FIG. 6 is an end view of an implantable medical device in accordancewith an embodiment of the present invention.

FIG. 7 is a graph of diameter recovery as a function of support coatingweight, for certain embodiments of the present invention.

FIG. 8 is a graph of diameter recovery as a function of gel contentwithin a support coating, for certain embodiments of the presentinvention.

FIG. 9 is a graph of COF values of certain embodiments of the presentinvention, as well as for known commercial self-expanding stents.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides for self-expanding medical implants thathave expansion characteristics and mechanical properties that renderthem suitable for a broad range of applications involving placementwithin bodily lumens or cavities. As used herein, “device” and “implant”are used synonymously. Also as used herein, “self-expanding” is intendedto include devices that are crimped to a reduced configuration fordelivery into a bodily lumen or cavity, and thereafter tend to expand toa larger suitable configuration once released from the deliveryconfiguration, either without the aid of any additional expansiondevices or with the partial aid of balloon-assisted orsimilarly-assisted expansion. When compared with conventionalself-expanding medical implants, the implants of the present inventionrecover to an exceptionally high percentage of their manufactureddiameter after being crimped and held in a small diameter for deliveryinto a bodily lumen. Moreover, when compared with conventionalself-expanding implants and particularly polymeric implants, theimplants of the present invention are characterized by much improvedstrength and other desired mechanical properties. As used herein,“strength” and “stiffness” are used synonymously to mean the resistanceof the medical implants of the present invention to deformation byradial forces. Examples of strength and stiffness measurements, as usedto characterize the medical implants of the present invention, includeradial resistive force and chronic outward force, as further definedherein.

In one embodiment shown in FIG. 1, the implant 100 preferably comprisesat least one strand woven together to form a substantially tubularconfiguration having a longitudinal dimension 130, a radial dimension131, and first and second ends 132, 133 along the longitudinaldimension. As used herein, “woven” is used synonymously with “braided.”For example, the tubular configuration may be woven to form a tubularstructure comprising two sets of strands 110 and 120, with each setextending in an opposed helix configuration along the longitudinaldimension of the implant. The sets of strands 110 and 120 cross eachother at a braid angle 140, that may be constant or may change along thelongitudinal dimension of the implant. Preferably, there are betweenabout 16 and about 96 strands used in the implants of the presentinvention, and the braid angle 140 is within the range of about 90degrees to about 135 degrees throughout the implant. The strands arewoven together using methods known in the art, using known weavepatterns such as Regular pattern “1 wire, 2-over/2-under”, Diamond halfload pattern “1 wire, 1-over/1-under”, or Diamond pattern “2 wire,1-over/1-under”.

Although the strands may be made from biostable polymeric or metallicmaterials, they are preferably made from at least one biodegradablepolymer that is preferably fully absorbed within about two years ofplacement within a patient, and more preferably within about one year ofplacement within a patient. In some embodiments, the strands are fullyabsorbed within about six or fewer months of placement within a patient.The first and second strand sets 110, 120 may be made from the same ordifferent biodegradable polymer. Non-limiting examples of biodegradablepolymers that are useful in the at least one strand of the presentinvention include poly lactic acid (PLA), poly glycolic acid (PGA), polytrimethylene carbonate (PTMC), poly caprolactone (PCL), poly dioxanone(PDO), and copolymers thereof. Preferred polymers are poly(lactic acidco-glycolic acid) (PLGA) having a weight percentage of up to about 20%lactic acid, or greater than about 75% lactic acid (preferably PLGA85:15), with the former being stronger but degrading in the body faster.The composition of PLGA polymers within these ranges may be optimized tomeet the mechanical property and degradation requirements of thespecific application for which the implant is used. For desiredexpansion and mechanical property characteristics, the materials usedfor the strands preferably have an elastic modulus within the range ofabout 1 to about 10 GPa, and more preferably within the range of about6-10 GPa.

To facilitate the low-profile aspects of the present invention (e.g.,the delivery of the implants into small diameter bodily lumens orcavities), the strands used in the implant 100 preferably have adiameter in the range of from about 125 microns to about 225 microns,and are more preferably less than about 150 microns in diameter. The useof small diameter strands results in an implant with minimal wallthickness and the preferred ability to collapse (i.e., to be crimped)within low diameter catheter delivery systems. Where multiple strandsare used, they may be of substantially equal diameters within thisrange, or first strand set 110 may be of a different general diameterthan second strand set 120. In either event, the diameters of strandsare chosen so as to render the implant 100 preferably deliverable from a10 French delivery catheter (i.e., 3.3 mm diameter) or smaller, and morepreferably from a 7 French delivery catheter (i.e., 2.3 mm diameter) orsmaller. The ability to place the implant of the present invention intosmall diameter delivery catheters allows for its implantation into smalldiameter bodily lumens and cavities, such as those found in thevascular, biliary, uro-genital, iliac, and tracheal-bronchial anatomy.Exemplary vascular applications include coronary as well as peripheralvascular placement, such as in the superficial femoral artery (SFA). Itshould be appreciated, however, that the implants of the presentinvention are equally applicable to implantation into larger bodilylumens, such as those found in the gastrointestinal tract.

In another embodiment of the present invention, the implant is anon-woven, self-expanding structure, such as a unitary polymericframework. As shown in FIG. 2, the non-woven implant 100 is preferablycharacterized by a regular, repeating pattern such as a latticestructure. The use of a unitary framework may provide a reduced profilewhen compared to the use of woven strands, which yield a minimum profilethat is the sum of the widths of overlapping strands. In addition, aunitary framework eliminates the possible change in length of theimplant associated with crimping and subsequent expansion, known asforeshortening, which is common in braided stents. When the implant 100is a unitary framework, it is fabricated using any suitable technique,such as by laser cutting a pattern into a solid polymer tube. In apreferred embodiment, when the implant 100 is a unitary framework, it isformed by laser cutting and includes a wall thickness of between about75 and about 100 microns. It should be recognized that while the presentinvention is described primarily with reference to woven strandconfigurations, aspects of the present invention are equally applicableto non-woven, self-expanding structures unless necessarily or expresslylimited to woven configurations.

There are a variety of strengthening means that are useful in thepresent invention to help provide the expansion and mechanicalproperties that are needed to render the implant 100 effective for itsintended purpose. Two measures of such mechanical properties that areused herein are “radial resistive force” (“RRF”) and “chronic outwardforce” (“COF”). RRF is the force that the implant applies in reaction toa crimping force, and COF is the force that the implant applies againsta static abutting surface. Without wishing to be bound by theory, theinventors believe that the self-expanding implants of the presentinvention should preferably recover to a high percentage of theiras-manufactured configuration after being crimped for insertion into thebody, and the thus expanded implant should have a relatively high RRF tobe able to hold open bodily lumens and the like, yet have a relativelylow COF so as to avoid applying possibly injurious forces against thewalls of bodily lumens or the like. For example, the implants of thepresent invention preferably expand to at least 90% of their asmanufactured configuration after being crimped, have an RRF of at leastabout 200 mm Hg, have an acute COF (at the time of delivery into abodily lumen or cavity) of about 40-200 mm Hg, and a COF of less thanabout 10 mm Hg after about 28 days in vivo.

In one embodiment, the strengthening means is a support coating 410 onat least one of the strands of the implant 100. Although referred toherein as a “coating,” the support coating 410 does not necessarily coatthe entire implant 100, and may not form a discrete layer over thestands or unitary framework of the implant 100; rather, the supportcoating 410 and underlying strands or unitary framework may beconsidered as a composite structure. The support coating 410 is madefrom an elastomeric polymer that, due to its elastic nature whencompressed or elongated, applies a force to implant 100 that acts infavor of radial expansion and axial contraction, thus enhancing radialstrength. The polymer of the support coating 410 is preferablybiodegradable. Alternatively, the support coating 410 is made from ashape memory polymer or a polymer that otherwise contracts upon heatingto body temperature. The inventors have surprisingly found that the useof support coatings on the polymeric implants of the present inventioncan result in the recovery of more than 90% of implant diameterpost-crimping, and yield significantly higher radial forces whencompared with uncoated implants or even with self-expanding metallicstents. The support coating 410 may be applied as a conformal coating(as shown in cross-section of an individual strand in FIG. 3), may bepartially applied to one or more individual strands such that thesupport coating 410 is applied to only a portion of the implant alongits longitudinal dimension, or may be applied to only the inner or outerdiameter of one or more individual strands. Also, the support coating410 may optionally vary in weight along the length of the implant; forexample, the ends of the implant may be coated with a thicker layer thanthe mid-section to provide added support to the ends of the implant. Inaddition, the support coating may accumulate at the crossover points or“nodes” of the woven device, which has the effect of aiding in diameterrecovery and the achievement of preferred COF and RRF values.

Examples of polymer materials used for the support coating 410 includesuitable thermoplastic or thermoset elastomeric materials that yield theelongation, mechanical strength and low permanent deformation propertieswhen combined with the implant strand(s). The inventors have foundexamples of suitable polymers to include certain random copolymers suchas poly(lactic acid-co-caprolactone) (PLCL),poly(glycolide-co-caprolactone) (PGCL), and poly(lacticacid-co-dioxanone) (PLDO), certain homopolymers such as polytrimethylene carbonate (PTMC), and copolymers and terpolymers thereof.Such polymers are optionally crosslinked with a crosslinker that is bi-or multi-functional, polymeric, or small molecule to yield a thermosetpolymer having a glass transition temperature (Tg) that is preferablylower than body temperature (37° C.), more preferably lower than roomtemperature (25° C.), and most preferably lower than about 5° C. Thethermoset elastomers provide a high elongation to break with lowpermanent deformation under cyclic mechanical testing.

In one preferred embodiment, the polymer material used for the supportcoating 410 is a biodegradable thermoset elastomer synthesized from afour arm PGCL polymer having a weight ratio of approximately 50:50 GA:CLthat is crosslinked with hexamethylene diisocyanate (HDI) to give apolyester with urethane crosslinks. Without wishing to be bound bytheory, the inventors believe that the combination of the elasticsegment (polyester portion) and the interactions (such as hydrogenbonding, allophanate or biuret formation) between the urethane segmentsof such polymers, in addition to a certain crosslinking density, yieldspreferred properties such as a high degree of elastic recovery undercyclic mechanical strain and high overall elasticity.

In other preferred embodiments, the support coating comprises PLCLhaving a weight ratio of approximately 50:50 PL:CL. In yet anotherpreferred embodiment, a PLCL 50:50 crosslinked with hexamethylenediisocyanate support coating is applied to a PLGA 75:25 braided implant.

The polymer material used for support coating 410 may be optimized fordesired mechanical properties. For example, the inventors have foundthat the molecular weight of such polymers may be manipulated to enhancecoating performance. As an example, when PLCL 50:50 crosslinked withhexamethylene diisocyanate is used as the support coating of the presentinvention, the inventors have found that a molecular weight (Mn) betweenabout 30 kDa and 100 kDa, preferably from 33 k to 65 k, results in alower modulus of elasticity and a higher strain to fracture, thus makingthe coating better able to adhere to a PLGA braided implant duringcrimping and post-crimping expansion and therefore less likely tofracture during deployment. Similarly, the inventors have found thatwhen PGCL 50:50 crosslinked with hexamethylene diisocyanate is used asthe support coating of the present invention, a molecular weight (Mn)from 8 kDa to 20 kDa does not yield an appreciable change in properties,but that a further increase in molecular weight to 50 kDa results in afour-fold increase in the strain at failure of the coating material. Assuch, a preferred range of molecular weight (Mn) for PGCL used in theimplants of the present invention is about 23 kDa to about 50 kDa.Additionally, the inventors have found that the viscosity of the spraycoating solution, the weight percent of crosslinker used in the spraycoating solution, and the temperature and duration of the supportcoating crosslinking process can be optimized to provide preferredcoating morphologies and radial forces.

The support coating 410 is coated onto the surface of the implant 100using any suitable method, such as spraying, dipping, electrospraying,rolling, and the like. If implant 100 is a woven structure, the supportcoating 410 may be applied to individual strands prior to forming thewoven structure, or to the woven structure after the formation thereof.In this case, owing to surface tension, the coating preferably collectsat intersection points between strands. If implant 100 is a non-wovenstructure, the support coating 410 may be applied, for example, to asolid polymer tube either before or after the removal of material suchas by laser cutting to form a patterned, non-woven structure.

The amount of support coating 410 applied to the implant 100 has beenidentified as one of the factors that contribute to the expansioncharacteristics and mechanical strength of the implant. Preferably, theapplication of the support coating 410 increases the weight of theuncoated implant 100 by about 20% to about 100%, more preferably, byabout 24% to about 70%, and most preferably by about 30% to about 60%.

In another embodiment, the strengthening means includes the attachmentof strand sets 110, 120 at one or more intersections of the strandsalong the longitudinal dimension of the implant 100. Such attachment maybe achieved by use of an adhesive, or by fusing the strands atpredetermined intersections such as by heat, laser, or ultrasound. Inthis embodiment, the strands comprise materials having sufficientelasticity such that the local strains induced by the adhesive/weldedjoints would not cause plastic deformation thereof.

In yet another embodiment, the strengthening means includes theincorporation of additives into one or more of the strands. In oneexample, such additives are neutralizing agents such as calcium salts(e.g., calcium carbonate or calcium phosphate) or other salts such asbarium salts that increase the mechanical strength of the strands intowhich they are incorporated, and further act to neutralize any acidicbyproducts resulting from the degradation of the strand material(s). Inanother example, such additives are plasticizers such as polyethyleneglycol (PEG) that dissolve from the strand(s) in vivo, thus increasingthe flexibility of the strand(s) and the implant over time.

In one embodiment, the implant 100 delivers one or more therapeuticagents at the site of implantation. The therapeutic agent(s) may beapplied to one or more strands for delivery therefrom in a number ofways. In one example, the therapeutic agent(s) are embedded within aconformal polymer coating 210 that adheres to one or more individualstrands of the implant 100. Such a coating 210 is preferably made from abiodegradable polymer admixed with the therapeutic agent(s) such thatthe agent is eluted from the polymer over time, or is released from thecoating as it degrades in vivo. In another example as shown in FIG. 4,one or more therapeutic agents are applied in discrete areas 220 on oneor more individual strands (shown as length of individual strand). Likecoating 210, discrete areas 220 are preferably made from a biodegradablepolymer admixed with the therapeutic agent(s) and eluted from thepolymer over time, or are released from the coating as it degrades invivo. In either of coating 210 or discrete areas 220, the biodegradablepolymer may be the same as or different from the biodegradablepolymer(s) used in the strands of the implant. In yet another example,the therapeutic agent(s) are admixed within the strand(s) of the implant100 such that the agent(s) are eluted from the one or more strands overtime, or are released from the one or more strands as the strand(s)degrade in vivo. In yet another example, the therapeutic agent(s) areadmixed within a support coating, as described herein. Likewise, inembodiments in which the implant 100 is a non-woven structure, thetherapeutic agent(s) may be admixed with the polymer used to fabricatethe implant 100.

The therapeutic agent(s) used in the present invention are any suitableagents having desired biological effects. For example, where the implantof the present invention is used to combat restenosis, the therapeuticagent is selected from anti-thrombogenic agents such as heparin, heparinderivatives, urokinase, and PPack (dextrophenylalanine proline argininechloromethylketone), enoxaparin, hirudin; anti-proliferative agents suchas angiopeptin, or monoclonal antibodies capable of blocking smoothmuscle cell proliferation, acetylsalicylic acid, paclitaxel, sirolimus,tacrolimus, everolimus, zotarolimus, vincristine, sprycel, amlodipineand doxazosin; anti-inflammatory agents such as glucocorticoids,betamethasone, dexamethasone, prednisolone, corticosterone, budesonide,estrogen, sulfasalazine, rosiglitazone, mycophenolic acid, andmesalamine; immunosuppressants such as sirolimus, tacrolimus,everolimus, zotarolimus, and dexamethasone;antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel,5-fluorouracil, cisplatin, vinblastine, cladribine, vincristine,epothilones, methotrexate, azathioprine, halofuginone, adriamycin,actinomycin and mutamycin; endostatin, angiostatin and thymidine kinaseinhibitors, and its analogs or derivatives; anesthetic agents such aslidocaine, bupivacaine, and ropivacaine; anti-coagulants such asD-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound,heparin, antithrombin compounds, platelet receptor antagonists,anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin(aspirin is also classified as an analgesic, antipyretic andanti-inflammatory drug), dipyridamole, hirudin, prostaglandininhibitors, platelet inhibitors and antiplatelet agents such as trapidilor liprostin, tick antiplatelet peptides; DNA demethylating drugs suchas 5-azacytidine, which is also categorized as a RNA or DNA metabolitethat inhibit cell growth and induce apoptosis in certain cancer cells;vascular cell growth promotors such as growth factors, VascularEndothelial Growth Factors (VEGF, all types including VEGF-2), growthfactor receptors, transcriptional activators, and translationalpromotors; vascular cell growth inhibitors such as antiproliferativeagents, growth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; cholesterol-lowering agents; vasodilating agents; and agentswhich interfere with endogenous vasoactive mechanisms; anti-oxidants,such as probucol; antibiotic agents, such as penicillin, cefoxitin,oxacillin, tobranycin; angiogenic substances, such as acidic and basicfibrobrast growth factors, estrogen including estradiol (E2), estriol(E3) and 17-Beta Estradiol; drugs for heart failure, such as digoxin,beta-blockers, angiotensin-converting enzyme (ACE) inhibitors includingcaptopril and enalopril, statins and related compounds; and macrolidessuch as sirolimus and everolimus. Preferred therapeutic agents used inthe present invention to treat restenosis and similar medical conditionsinclude sirolimus, everolimus, zotarolimus, vincristine, sprycel,dexamethasone, and paclitaxel. Also preferred is the use of agents thathave a primary mechanism of action of inhibiting extracellular matrixremodeling, and a secondary mechanism of action of inhibiting cellproliferation. Such agents include 5-fluorouracil, valsartan,doxycyclin, carvedilol, curcumin, and tranilast.

Coating 210 or areas 220 containing one or more therapeutic agents areapplied to implant 100 by any suitable method, such as spraying,electrospraying, rolling, dipping, chemical vapor deposition, andpotting. As an alternate embodiment, coating 210 or areas 220 is furthercoated with a biodegradable topcoat as shown in FIG. 5 (individualstrand shown in cross-section), that acts to regulate the delivery ofthe therapeutic agent from coating 210 or areas 220 into bodily tissue.In one embodiment, the topcoat 211 acts as a diffusion barrier such thatthe rate of delivery of the therapeutic agent(s) are limited by the rateof its diffusion through the topcoat 211.

In another embodiment, the therapeutic agent(s) cannot diffuse throughthe topcoat 211 such that delivery thereof is simply delayed until thedegradation of the topcoat 211 is complete. The topcoat 211 preferablycomprises a biodegradable polymer that is the same as or different fromthat of the coating 210 or the strands. If implant 100 is a wovenstructure, coatings 210, 220, or 211 may be applied to individualstrands prior to forming into the woven structure, or to the wovenstructure after the formation thereof. If implant 100 is a non-wovenstructure, coatings 210, 220, or 211 may be applied, for example, to asolid polymer tube either before or after the removal of material suchas by laser cutting to form a patterned, non-woven structure. Inembodiments that include support coating 410, the coatings 210, 220,and/or 211 are preferably applied over such support coating 410, or thesupport coating 410 itself may include the therapeutic agent(s).

The implant 100 of the present invention is self-expanding in that it ismanufactured at a first diameter, is subsequently reduced or “crimped”to a second, reduced diameter for placement within a delivery catheter,and self-expands towards the first diameter when extruded from thedelivery catheter at an implantation site. The first diameter ispreferably at least 20% larger than the diameter of the bodily lumeninto which it is implanted. The implant 100 is preferably designed torecover at least about 80% and up to about 100% of its manufactured,first diameter. The inventors have found that implants in accordancewith the present invention have a recovery diameter greater than 80%,and preferably greater than 90%, of the manufactured, first diameterafter being crimped into exemplary delivery catheters of either 1.8 mmor 2.5 mm inner diameter and held for one hour at either roomtemperature (25° C.) or body temperature (37° C.). Such implants abraided structure comprising 32 strands ranging in size from 0.122 mm to0.178 mm, braided with an inner diameter ranging from 5 to 6 mm. In apreferred embodiment, the implant 100 has a manufactured, first diameter(inner) of about 4.0 mm to about 10.0 mm.

Various factors contribute to the radial strength of implant 100. Forwoven implant structures, these factors include the diameter(s) of thestrands, the braid angle 140, the strand material(s), the number ofstrands used, and the use of strengthening means. The inventors havefound that it is preferred that the woven implants of the presentinvention have a braid angle 140 within a range of about 90° to 135°,more preferably within a range of about 110° to 135°, and mostpreferably within a range of about 115° to 130°. The inventors haveconfirmed through experimentation that braid angle may affect certainmechanical properties of the implants of the present invention. Forexample, the inventors have found that while a braid angle of 110° for 6mm PGCL coated braided implants made from PLGA 10:90 copolymer strandsyields post-crimp RRF and COF values at 4.5 mm of 370 mm and 147 mm Hg,respectively, the same coated implants having a 127° braid angle arecharacterized by post-crimp RRF and COF values at 4.5 mm of 900 mm and170 mm Hg, respectively. RRF and COF values for 7 mm PGCL coated PLGA10:90 copolymer implants having a 140° braid angle were not obtainablebecause the samples buckled in the test equipment, thus demonstratingthat a high braid angle may result in the inability of the implant touniformly collapse during crimping into a catheter. Braid angle was alsofound to have an effect upon the ability of the implants of the presentinvention to recover to their as-manufactured diameters. For example, 7mm PGCL coated braided implants made from PLGA 10:90 copolymer andhaving braid angles of 133°, 127°, and 110° were found to recover toabout 96%, 94%, and 91% of their as-manufactured configurations,respectively, after being held at 37° C. for one hour.

In another embodiment specific to woven structures, the ends of strandsare fused in patterns on the outside and/or inside of the implant 100,as shown in FIG. 6. Fusing the strands in this manner causes the ends132, 133 to flare outwards instead of curling inward, thus addressing aphenomenon in which the ends of the implant may naturally curl inwardwhen the implant is crimped into a reduced configuration for insertioninto a bodily lumen or cavity. In one embodiment, the ends are fused inpatterns such that their final positions are axially staggered. Strandsare fused, for example, by using heat, chemicals, adhesives, crimpswages, coatings (elastomeric or non-elastomeric), or other suitablefusing or joining techniques.

The implants of the present invention are preferably radiopaque suchthat they are visible using conventional fluoroscopic techniques. In oneembodiment, radiopaque additives are included within the polymermaterial of one or more strands of implant 100. Examples of suitableradiopaque additives include particles comprising iodine, bromine,barium sulfate, and chelates of gadolinium or other paramagnetic metalssuch as iron, manganese, or tungsten. In another embodiment, theradiopaque groups, such as iodine, are introduced onto the polymerbackbone. In yet another embodiment, one or more biostable orbiodegradable radiopaque markers, preferably comprising platinum,iridium, tantalum, and/or palladium are produced in the form of a tube,coil, sphere, or disk, which is then slid over one or more strands offiber to attach to the ends of implant 100 or at other predeterminedlocations thereon. When the marker is in the form of a tube or coil, ithas a preferable wall thickness of about 0.050 to 0.075 mm and a lengthof about 0.3 to 1.3 mm. The tube is formed by extrusion or other methodsknown in the art. The coil is formed by winding a wire around a mandrelof desired diameter and setting the coil with heat or other methodsknown in the art.

To facilitate delivery, the implant 100 is preferably loaded into adelivery catheter just prior to being implanted into a patient. Loadingthe implant 100 in close temporal proximity to implantation avoids thepossibility that the polymer of the implant 100 will relax duringshipping, storage, and the like within the delivery catheter andtherefore cannot fully expand to a working configuration. As such, oneaspect of the invention includes a method of delivering an implant ofthe invention that comprises the step of loading the implant into adelivery catheter within a short period of time, and preferably withinone hour, before implantation into a body lumen. It should be noted,however, that it is not required that the implants of the presentinvention are loaded into delivery catheters just prior to beingimplanted. In fact, one advantage of the present invention is that itprovides self-expanding implantable medical devices with preferredexpansion characteristics and mechanical properties even after beingloaded in a delivery catheter for prolonged periods.

The present invention is further described with reference to thefollowing non-limiting examples.

Example 1

Braided implants were manufactured using a PLGA 10:90 copolymer byspooling fiber spun monofilaments onto individual bobbins. Each bobbinwas placed on a braiding machine, strung through rollers and eyelets andwrapped around a mandrel. The braiding tension of the machine was setfor the size of the monofilament (i.e., 70 g min, 215 g max for 0.005″fiber). The pix/inch was set to obtain an ideal angle to maximize radialstrength but still allow the braid to be removed from the mandrel (i.e.,110 to 135 degrees for a 6 mm mandrel). The braid pattern was selectedand the monofilaments were braided off the spool onto the mandrel by thebraiding machine. Tiewraps were used on the end of each mandrel to keepthe tension on the filaments, which can be important for heat annealingand obtaining high modulus properties. The braided polymer was heatannealed on the mandrel, and then cut into desired lengths with a bladeand removed from the mandrel. A representative implant was measured tohave an outer diameter of about 6.0 mm and a length of about 20 mm.

Implants were coated with a support coating made frompoly(glycolide-co-caprolactone) (PGCL) cured with hexamethylenediisocyanate. The PGCL 50:50 copolymer was prepared as follows. A 100 mLround-bottom flask was dried in oven at 110° C. and then cooled to roomtemperature under a nitrogen atmosphere. The flask was charged withSn(Oct)₂ (15 mg), pentaerythritol (68 mg), glycolide (10.0 g), ands-caprolactone (10.0 g), respectively. Subsequently, the flask wasequipped with a magnetic stir bar and a three-way valve connected to anitrogen balloon. The flask was thoroughly degassed under reducedpressure and flushed with nitrogen. The flask was then placed into anoil bath which was preheated to 170° C. The reaction was stirred at 170°C. for 24 h under a nitrogen atmosphere. After cooling to roomtemperature, the solid obtained was dissolved in dichloromethane andprecipitated from anhydrous diethyl ether. The solution was decanted andthe residual sticky solid was washed thoroughly with diethyl ether anddried in vacuum. Typically, around 18 g of polymer was recovered throughthe purification. GPC characterization revealed a number averagemolecular weight (Mn) of 39,900 and a polydispersity index (PDI) of1.23.

The four-arm PGCL 50:50 (1.0 g) and HDI (375 μL) were dissolved in 20 mLdichloromethane to make a stock solution for spray-coating. A steelmandrel of 2 mm in diameter was mounted vertically onto a mechanicalstirrer, and the braided implant was placed over the mandrel. A spraygun (Badger 150) was arranged perpendicular to the mandrel, andconnected to a nitrogen cylinder and a reservoir containing the stocksolution. The mechanical stirrer was turned on to spin the mandrel andthe solution was sprayed onto the braid by applying the nitrogen flow.The coating weight could be controlled by the spray time. After spraycoating, devices were dried in air for 1 h and then cured at 100° C. for16 h. A catalyst such as tin octanoate or zinc octanoate may also beused in the curing process to reduce the curing time and/or temperature.

Coated devices were placed in an MSI radial force tester to obtain RRFand COF values, both measured in mm Hg, at time points prior to andsubsequent to crimping the device to 2.5 mm.

The inventors surprisingly found that whereas uncoated implants wereable to recover to only about 50% of their original diameter after beingcrimped at 37° C. for one hour, the application of the PGCL/HDI coatingresulted in a recovery of up to about 95% of the device originaldiameter. This effect was found to be at least partially dependent uponthe coating weight on the implant. As illustrated in FIG. 7, diameterrecovery was found to be related to the mass increase attributable tothe application of the coating (i.e., coating weight), with anappreciable increase in the diameter recovery ability beginning when theincrease in implant mass due to the application of the coating is about15%. The effect of coating weight levels off when the increase inimplant mass due to the application of the coating is at least about20%, at which point the device recovery diameter is at least about 90%.

Implant diameter recovery was also affected by the percent gel contentin the coating, as shown in FIG. 8. Gel content is defined as thequantity of coating that is sufficiently crosslinked so that it is nolonger soluble in a solvent. The calculation of gel content in thePGCL/HDI coating is described in Example 3. The inventors have found inthis Example that a coating gel content of greater than about 80% ispreferred to achieve a diameter recovery of at least about 90%.

Table I shows the percent recovery, radial resistive force (RRF) at apost-crimp diameter of 4.5 mm, and chronic outward force (COF) at apost-crimp diameter of 4.5 mm, for coated implants with varying coatingweight. As can be seen from the data in Table I, the support coatingincreased the post-crimp recovery ability, RRF, and COF of the implants.Moreover, in addition to increasing recoverability of the implantacutely (i.e., after being crimped one hour in a 37° C. water bath), thesupport coating is able to increase recoverability chronically (i.e.,after being crimped for five days at room temperature in air).

TABLE I Percent recovery, RRF, and COF for coated implant samples thatwere crimped to 2.5 mm and held in water bath at 37° C. The percentincrease in implant weight due to the coating is shown in the SampleDescription column. Water % Recovery RRF at COF at Sample Sample Bathafter 2.5 mm 4.5 mm 4.5 mm No. Description Treatment Crimp (mmHg) (mmHg)1 10:90 PLGA 1 hour 48 83.4 11.6 uncoated 2 10:90 PLGA 1 hour 93.5 — —coated 45% 3 10:90 PLGA 1 hour 94.5 645.0 245.0 coated 41% 4 10:90 PLGA1 hour 94.6 — — coated 33% 5 10:90 PLGA 5 days at 94.4 — — coated 33%room T in air (no water bath) 6 10:90 PLGA 1 hour 91.5 1030.0 188.0coated 24% 7 10:90 PLGA 1 hour 77.9 897.0 84.0 coated 22% 8 10:90 PLGA 1hour 65.6 559.0 24.4 coated 17% 9 10:90 PLGA 1 hour 58.2 — — coated 15%10 10:90 PLGA 1 hour 51.4 393.0 −2.6 coated 13% 11 PDO 1 hour 79.0 53.40 uncoated 12 PDO coated 1 hour 83.6 863.0 115.0 37%

Example 2

Implants and coating solutions were manufactured as described inExample 1. Instead of being applied uniformly to the implants, supportcoatings were applied to just the ends of the implants (i.e.,approximately 4-5 mm at each end). Whereas the uncoated implant was ableto recover only about 48% of its original diameter after being crimpedto 2.5 mm and held in a water bath for one hour at 37° C., the implantcoated at its ends was able to recover, under the same conditions, toabout 82% of its original diameter. Moreover, for these same implants,the RRF and COF was increased from 83.4 mmHg and 11.6 mmHg to 595.0 mmHgand 55.0 mmHg, respectively.

Example 3

The gel content of a coated implant (such as the implant described inExample 1) was measured via extraction. The PGCL/HDI coated device wasplaced in 5 mL of dichlormethane and shaken at room temperature forabout 1 hour. The solvent was removed, and the device was rinsedthoroughly with dichloromethane and subsequently allowed to air dry forabout 10 minutes. The device was placed in a convection oven at 100° C.to remove any residual solvent. The gel content in the coating was thendetermined using the following equation: % gel content in coating=((massof coated device after extraction−mass of uncoated device)/(mass ofcoated device before extraction−mass of uncoated device))×100. A controlexperiment on the uncoated woven PLGA 10:90 structure showed noappreciable mass loss in a similar experiment.

Example 4

A pattern was laser cut into a tubular base material to produceself-expanding medical implants. Some of the implants were coated with asupport coating made from PGCL cured with HDI, as described inExample 1. Similar to the previous examples, coated implantsdemonstrated higher RRF and COF properties as compared with uncoatedimplants.

Example 5

Braided implants having an as-manufactured diameter of 6 mm weremanufactured using a PLGA 75:25 copolymer using a manufacturing processsimilar to that of Example 1. The implants were coated with a supportcoating made from PLCL 50:50 prepared as follows. A 250 mL round-bottomflask was dried in an oven at 110° C. and cooled to room temperature ina nitrogen atmosphere. The flask was charged with Sn(Oct)₂ (11.5 mg),pentaerythritol (204 mg), lactide (30.0 g), and ε-caprolactone (30.0 g),respectively. Subsequently, the flask was equipped with a magnetic stirbar and a three-way valve connected to a nitrogen balloon. The flask wasthoroughly degassed under reduced pressure and flushed with nitrogen.The flask was then placed into an oil bath which was preheated to 170°C. The reaction was stirred at 170° C. for 48 h under a nitrogenatmosphere. After cooling to room temperature, the highly viscous liquidobtained was dissolved in approximately 200 mL dichloromethane andprecipitated from 1200 mL anhydrous diethyl ether. The solution wasdecanted and the residual sticky polymer was washed thoroughly withdiethyl ether and dried under vacuum. Typically, around 48 g polymer wasrecovered through the purification. GPC characterization revealed anumber average molecular weight (Mn) of 52,500 and a polydispersityindex (PDI) of 1.2.

Coated devices were crimped to 1.85 mm in a MSI radial force tester(Model# RX550-100) to obtain RRF and COF values, both measured in mm Hg,at a diameter of 4.5 mm for 6 mm device and at a diameter of 5.5 mm for7 mm device. Like the implants coated with PGCL described in Example 1,both RRF and COF were found to be directly proportional to the coatingweight. The inventors note that both RRF and COF for the coated devicesare significantly higher than for uncoated devices. For example, a 7 mmimplant having an increase in weight due to the PLCL/HDI coating ofabout 45% resulted in RRF of about 450 mm Hg and COF of 90 mm Hg,measured at 4.5 mm, while the uncoated device resulted in RRF and COF of80 mm and 0 mm Hg, respectively.

Example 6

Braided implants having an as-manufactured diameter of 6 mm weremanufactured using a PLGA 75:25 copolymer using a manufacturing processsimilar to that of Example 1. The implants were coated with a supportcoating made from poly trimethylene carbonate (PTMC) andhexamethylenediisocyante. The PTMC three arm polymer was prepared asfollows. A 100 mL round-bottom flask, previously dried under heat andvacuum, was charged with Sn(Oct)₂ (20 mg), triethanolamine (298.4 mg)and trimethylene carbonate (30 g) respectively. Subsequently, the flaskwas equipped with a magnetic stir bar and a three-way valve connected toa nitrogen balloon. The flask was thoroughly degassed under reducedpressure and flushed with nitrogen and then placed into an oil bathwhich was preheated to 70° C. The oil bath temperature was thenincreased to 100° C. over 15 minutes. The reaction was stirred at 100°C. for 23 h under a nitrogen atmosphere. After cooling to roomtemperature, the viscous liquid obtained was dissolved overnight inapproximately 50 mL dichloromethane and subsequently precipitated from550 mL ethanol. The precipitated polymer was stirred for one hour afterwhich the ethanol was decanted. The process of dissolving the polymer indichloromethane and precipitating in ethanol was repeated. The polymerwas then dissolved in dichloromethane, precipitated into 550 mL diethylether and stirred for one hour after which time the diethyl ether wasdecanted. The polymer was then dried under vacuum @ 70° C. for a periodof 72 hours. Typically 24 g of polymer was recovered using aboveprocess. GPC characterization of the final polymer revealed a numberaverage molecular weight (Mn) of 29 kDa and a polydispersity index (PDI)of 2.0.

An MSI radial force tester (Model# RX550-100) was used to obtain radialresistive force (“RRF”) and chronic outward force (“COF”), at apost-crimp diameter of 4.5 mm for PTMC/HDI coated devices. For example,a 6 mm implant having an increase in weight due to the PTMC/HDI supportcoating of about 50% resulted in RRF of 490 mm Hg and COF of 83 mm Hg,measured at 4.5 mm. PTMC is considered to be a surface-degradingmaterial which does not generate acidic byproducts upon degradation.

Example 7

A support coating solution was prepared by dissolving 1.0 g of PLCL50:50 copolymer (Mn=67 kDa) in 19.875 mL of methylene chloride.Subsequently, 0.125 mL of hexamethylene diisocyanate is added to thesolution, which was then transferred to a 60 mL polypropylene syringeusing a 14 gauge needle. No catalyst was added to the support coatingsolution at any time.

The support coating solution was sprayed onto PLGA 85:15 braidedimplants. After spray coating, the implants were allowed to dry for upto 60 minutes in a nitrogen atmosphere. The implants were thentransferred to a curing oven for a two-step curing process consisting ofa first step at 75° C. for 16 hours, followed by a second step at 100°C. for a minimum of 96 hours.

Comparative Example 1

Implants of the present invention were compared to several commerciallyavailable, biostable self-expanding implants, namely the VIABAHN®Endoprosthesis (a self-expanding nitinol stent-graft from W.L. Gore &Associates, Inc.), the S.M.A.R.T.® stent (a self-expanding nitinol stentfrom Cordis Corp.), and the WALLSTENT® Endoprosthesis (a self-expandingsteel stent from Boston Scientific Corp.). Specifically, the RRF and COFvalues of these commercially available implants were measured andcompared with 6 mm (having a 127° braid angle) and 7 mm (having braidangles of 127° and 110°) diameter implants made from PLGA 75:25. ThePLGA implants were made using a manufacturing process similar to that ofExample 1, and coated with a support coating made from PLCL 50:50copolymer and hexamethylenediisocyanate as described in Example 5 with acoating weight of between 44% and 50% for the 7 mm devices and a weightof 47% to 57% for the 6 mm devices. RRF and COF values were measured atpost-crimp diameters corresponding to the range of intended targetvessel diameters. The results demonstrated that the implants of thepresent invention are characterized by mechanical properties such as RRFand COF that are comparable to their commercially available metalliccounterparts.

Comparative Example 2

Braided implants having an as-manufactured diameter of 6 mm weremanufactured using a PLGA 75:25 copolymer using a manufacturing processsimilar to that of Example 1. One set of implants were coated with asupport coating comprising PGCL 50:50 and hexamethylenediisocyanate, andanother set of implants were coated with a support coating comprisingPLCL 50:50 and hexamethylenediisocyanate. The implants were deployedinto vessel-compliant tubing and maintained at 37° C. under simulatedflow conditions for 0, 7, 14, and 28 days. At those time points, theimplants were explanted from the tubing, dried overnight, and the COF ofthe implants was measured at a post-crimp diameter of 4.5 mm. Theresults are shown in FIG. 9, which demonstrate that the COF for bothsets of implants decrease over time, with COF going to zero for the PGCLcoated implants as of 28 days. Also shown in FIG. 9 are the COF valuesmeasured for the S.M.A.R.T. stent and WALLSTENT Endoprosthesis asdescribed in Comparative Example 1, which are constant because thosedevices are metallic and do not degrade or relax over time. Theinventors believe that the significant decrease in COF over time for theimplants of the present invention is an advantage over their metallicstent counterparts because a continuous force applied by implantsagainst surrounding tissue over time may result in chronic irritationand inflammation leading to restenosis.

The present invention provides woven and non-woven self-expandingmedical implants for placement within a bodily lumen that havesufficient strength and other mechanical properties that are necessaryto effectively treat a variety of medical conditions. While aspects ofthe invention have been described with reference to example embodimentsthereof, it will be understood by those skilled in the art that variouschanges in form and details may be made therein without departing fromthe scope of the invention.

1. A polymer coating composition prepared by a process comprising thesteps of: dissolving poly (lactic acid-co-caprolactone) in a solvent toform a solution; adding a diisocyanate crosslinker to the solution; andcuring said solution; wherein said solution does not comprise acatalyst.
 2. The polymer coating composition of claim 1, wherein saiddiisocyanate crosslinker is hexamethylene diisocyanate.
 3. The polymercoating composition of claim 1, wherein said poly (lacticacid-co-caprolactone) comprises about 50 weight percent of lactic acidand about 50 weight percent of caprolactone.
 4. The polymer coatingcomposition of claim 1, wherein said solution comprises about 0.125 mLof said diisocyanate crosslinker to every 1.0 grams of poly (lacticacid-co-caprolactone).
 5. The polymer coating composition of claim 4,wherein said diisocyanate crosslinker is hexamethylene diisocyanate. 6.The polymer coating composition of claim 4, wherein said solutioncomprises about 19.875 mL of a solvent to every 1.0 grams of poly(lactic acid-co-caprolactone).
 7. The polymer coating composition ofclaim 6, wherein said solvent comprises methylene chloride.
 8. A medicalimplant comprising a coating, said coating prepared by a processcomprising the steps of: dissolving poly (lactic acid-co-caprolactone)in a solvent to form a solution; adding a diisocyanate crosslinker tothe solution; and curing said solution; wherein said solution does notcomprise a catalyst.
 9. The medical implant of claim 8, wherein saiddiisocyanate crosslinker is hexamethylene diisocyanate.
 10. The medicalimplant of claim 8, wherein said poly (lactic acid-co-caprolactone)comprises about 50 weight percent of lactic acid and about 50 weightpercent of caprolactone.
 11. The medical implant of claim 8, whereinsaid solution comprises about 0.125 mL of said diisocyanate crosslinkerto every 1.0 grams of poly (lactic acid-co-caprolactone).
 12. Themedical implant of claim 11, wherein said diisocyanate crosslinker ishexamethylene diisocyanate.
 13. The medical implant of claim 11, whereinsaid solution comprises about 19.875 mL of a solvent to every 1.0 gramsof poly (lactic acid-co-caprolactone).
 14. The medical implant of claim13, wherein said solvent comprises methylene chloride.
 15. The medicalimplant of claim 8, wherein said implant comprises polymeric strandscoated with said coating.
 16. The medical implant of claim 15, whereinsaid strands comprise poly(lactic acid co-glycolic acid).
 17. Themedical implant of claim 16, wherein said poly(lactic acid co-glycolicacid) comprises about 85 weight percent of lactic acid and about 15weight percent of glycolic acid.
 18. A medical implant comprising acoating, said implant prepared by a process comprising the steps of:providing an implant comprising braided polymeric strands; dissolvingpoly (lactic acid-co-caprolactone) in a solvent to form a solution;adding a diisocyanate crosslinker to the solution; coating said solutiononto said polymeric strands; and curing said solution; wherein saidsolution does not comprise a catalyst.
 19. The medical implant of claim18, wherein said polymeric strands are biodegradable.
 20. The medicalimplant of claim 19, wherein said strands comprise poly(lactic acidco-glycolic acid).
 21. The medical implant of claim 20, wherein saidpoly(lactic acid co-glycolic acid) comprises about 85 weight percent oflactic acid and about 15 weight percent of glycolic acid.
 22. Themedical implant of claim 18, wherein said diisocyanate crosslinker ishexamethylene diisocyanate.
 23. The medical implant of claim 18, whereinsaid poly (lactic acid-co-caprolactone) comprises about 50 weightpercent of lactic acid and about 50 weight percent of caprolactone. 24.The medical implant of claim 18, wherein said solution comprises about0.125 mL of said diisocyanate crosslinker to every 1.0 grams of poly(lactic acid-co-caprolactone).
 25. The medical implant of claim 24,wherein said diisocyanate crosslinker is hexamethylene diisocyanate.